The Winged Helix Domain of CSB Regulates RNAPII Occupancy at Promoter Proximal Pause Sites.

Nicole L Batenburg, Shixin Cui, John R Walker, Herb E Schellhorn, Xu-Dong Zhu

International journal of molecular sciences 2021 Mar 25

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Cockayne syndrome group B protein (CSB), a member of the SWI/SNF superfamily, resides in an elongating RNA polymerase II (RNAPII) complex and regulates transcription elongation. CSB contains a C-terminal winged helix domain (WHD) that binds to ubiquitin and plays an important role in DNA repair. However, little is known about the role of the CSB-WHD in transcription regulation. Here, we report that CSB is dependent upon its WHD to regulate RNAPII abundance at promoter proximal pause (PPP) sites of several actively transcribed genes, a key step in the regulation of transcription elongation. We show that two ubiquitin binding-defective mutations in the CSB-WHD, which impair CSB's ability to promote cell survival in response to treatment with cisplatin, have little impact on its ability to stimulate RNAPII occupancy at PPP sites. In addition, we demonstrate that two cancer-associated CSB mutations, which are located on the opposite side of the CSB-WHD away from its ubiquitin-binding pocket, impair CSB's ability to promote RNAPII occupancy at PPP sites. Taken together, these results suggest that CSB promotes RNAPII association with PPP sites in a manner requiring the CSB-WHD but independent of its ubiquitin-binding activity. These results further imply that CSB-mediated RNAPII occupancy at PPP sites is mechanistically separable from CSB-mediated repair of cisplatin-induced DNA damage.

Citation

Nicole L Batenburg, Shixin Cui, John R Walker, Herb E Schellhorn, Xu-Dong Zhu. The Winged Helix Domain of CSB Regulates RNAPII Occupancy at Promoter Proximal Pause Sites. International journal of molecular sciences. 2021 Mar 25;22(7)